CARCINOGENICITY OF THE DRINKING-WATER MUTAGEN CHLORO-4-(DICHLOROMETHYL)-5-HYDROXY-2(5H)-FURANONE IN THE RAT

Background: Several epidemiologic studies have suggested that the cons umption of chlorinated drinking water may be associated with the devel opment of certain cancers in humans, 3-Chloro-4-(dichloromethyl)-5-hyd roxy-2 (5H)-furanone (MX), a byproduct of the chemical reactions that occur in chlorinated drinking water, has been found to be mutagenic in bacteria and mammalian cells; however, its potential to cause tumors in animals has not been tested previously, Purpose: The objective of t his study was to evaluate the carcinogenicity of MX in rats given MX i n their drinking water. Methods: MX was administered to male and femal e Wistar rats (50 rats per dose group) in drinking mater for 104 weeks at concentrations yielding the average daily doses of MX of 0.4 mg/kg of animal weight (low dose), 1.3 mg/kg (mid dose), and 5.0 mg/kg (hig h dose) for males and 0.6 mg/kg, 1.9 mg/kg, and 6.6 mg/kg for females, respectively. Control rats received water from the same source used f or preparation of the MX dose formulations (after its adjustment to th e same pH range), Body; Freight, clinical signs, and food and mater co nsumption were recorded regularly, At the end of the treatment period, the animals were killed and full histopathologic analysis was perform ed on 47 tissues and all lesions, Results: Dose-dependent increases in tumor incidence were observed in rats given MX-containing drinking wa ter; the same MX doses had no obvious toxic effects on animals, MX con sumption increased most drastically the prevalence of follicular adeno ma (up to 43% and 72% in high-dose males and females, a test [one-side d] for positive trend in all dose groups P = .0045 and P = .0000, resp ectively) and carcinoma (55% [P = .0000] and 44% [P = .0000], respecti vely) in thyroid glands and cholangioma in the liver (8 % [P = .0009] and 66% [P =.0000] in the high-dose males and females, respectively), Among rats given the higher doses of MX in their drinking water, corti cal adenomas of the adrenal glands were increased in both sexes, alveo lar and bronchiolar adenomas of the lungs and Langerhans' cell adenoma s of the pancreas were increased in males, and lymphomas, leukemias, a nd adenocarcinomas and fibroadenomas of the mammary glands were increa sed in females, Even tile lowest MX dose studied was carcinogenic. Con clusion: MX is a potent carcinogen in both male and female rats, and i t causes tumors at doses that are not overtly toxic to rats, Implicati ons: Although these findings cannot be extrapolated to humans, MX shou ld be studied as a candidate risk factor in the possible association b etween consumption of chlorinated drinking water and cancer in humans.